基于结构的蛋白质酪氨酸磷酸酶抑制剂的设计与发现，其包含新型异噻唑烷酮杂环磷酸酪氨酸模拟物。
Structure-based design and discovery of protein tyrosine phosphatase inhibitors incorporating novel isothiazolidinone heterocyclic phosphotyrosine mimetics.
作者信息
Combs Andrew P, Yue Eddy W, Bower Michael, Ala Paul J, Wayland Brian, Douty Brent, Takvorian Amy, Polam Padmaja, Wasserman Zelda, Zhu Wenyu, Crawley Matthew L, Pruitt James, Sparks Richard, Glass Brian, Modi Dilip, McLaughlin Erin, Bostrom Lori, Li Mei, Galya Laurine, Blom Karl, Hillman Milton, Gonneville Lucie, Reid Brian G, Wei Min, Becker-Pasha Mary, Klabe Ronald, Huber Reid, Li Yanlong, Hollis Gregory, Burn Timothy C, Wynn Richard, Liu Phillip, Metcalf Brian
机构信息
Discovery Chemistry, Incyte Corporation, Experimental Station, E336/132A, Route 141 and Henry Clay Road, Wilmington, DE 19880, USA.
出版信息
J Med Chem. 2005 Oct 20;48(21):6544-8. doi: 10.1021/jm0504555.
Structure-based design led to the discovery of novel (S)-isothiazolidinone ((S)-IZD) heterocyclic phosphotyrosine (pTyr) mimetics that when incorporated into dipeptides are exceptionally potent, competitive, and reversible inhibitors of protein tyrosine phosphatase 1B (PTP1B). The crystal structure of PTP1B in complex with our most potent inhibitor 12 revealed that the (S)-IZD heterocycle interacts extensively with the phosphate binding loop precisely as designed in silico. Our data provide strong evidence that the (S)-IZD is the most potent pTyr mimetic reported to date.
基于结构的设计促使发现了新型的（S）-异噻唑烷酮（（S）-IZD）杂环磷酸酪氨酸（pTyr）模拟物，将其掺入二肽中时，是蛋白酪氨酸磷酸酶1B（PTP1B）的异常强效、竞争性和可逆抑制剂。PTP1B与我们最有效的抑制剂12形成的复合物的晶体结构表明，（S）-IZD杂环与磷酸盐结合环广泛相互作用，这与计算机模拟设计完全一致。我们的数据提供了强有力的证据，证明（S）-IZD是迄今为止报道的最有效的pTyr模拟物。
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